Patent EP-1731511-A1 (EP)
Inventor: HIMMELSBACH FRANK
IPC: C07D215/42
Filed: 2000-06-16
Abstract: Substituted amino-quinoline and amino-quinazoline derivatives are new. Substituted amino-quinoline and amino-quinazoline derivatives of formula (I) and their tautomers, stereoisomers and salts are new. [Image] R aH or 1-4C alkyl; R bPh, Ph-CH 2-, or -CH(Ph)-CH 3-; Ph : phenyl substituted by R 1-R 3; R 1, R 2H, halo, 1-4C alkyl, OH, 1-4C alkoxy, 3-6C cycloalkyl, 4-6C cycloalkoxy, 2-5C alkenyl, 2-5C alkynyl, Ar, Ar-O-, Ar-CH 2-, Ar-O-CH 2-, 3-5C alkenyloxy, 3-5C alkynyloxy, 1-4C alkylthio, 1-4C alkyl-SO-, 1-4C alkyl-SO 2-, CF 3-S-, CF 3-SO-, CF 3-SO 2-, CH 3 or OCH 3 substituted with 1-3 F, C 2H 5 or OCH 2H 5 substituted by 1-5 F, CN, NO 2, NH 2, (1-4C alkyl)NH-, or (1-4C alkyl) 2N-; or R 1 + R 2 on adjacent C atoms : -CH = CH-CH=CH-, -CH=CH-NH- or -CH=N-NH-; R 3H, F, Cl, Br, 1-4C alkyl, CF 3, or 1-4C alkoxy; X : C(CN) or N; A : imino optionally substituted by 1-4C alkyl; B : C(O) or SO2; C : 1,3-allenylene, 1,1-vinylene or 1,2-vinylene (all optionally substituted by CF 3 or 1-2 CH 3), ethynylene, or 1,3-butadien-1,4-ylene optionally substituted by CF 3 or 1-4 CH 3; D : 1-8C alkylene, -CO-1-8C alkylene or -SO 2-1-8C alkylene (optionally substituted by 1-4F), -CO-O-1-8C alkylene, -CO-NR 4-1-8C alkylene, or -SO 2-NR 4-1-8C alkylene; or D : bond when attached to a C atom of E or CO or SO2 when attached to a N atom of E; E : NH 2, or (1-4C alkyl)NH-, (1-4C alkyl) 2N-, (2-4C alkyl)NH-, (1-4C alkyl)(2-4C alkyl)N- or (2-4C alkyl) 2N- (all substituted in the beta -, gamma - or delta -position by R 5), (3-7C cycloalkyl)NH- or (3-7C cycloalkyl-1-3C alkyl)NH- (all optionally N-substituted by 1-4C alkyl), NH 2 or (1-4C alkyl)NH- (all optionally N-substituted by tetrahydrofuran-3-yl, tetrahydropyran-(3 or 4)-yl, tetrahydrofuranylmethyl, 1-(tetrahydrofuran-3-yl)-piperidin-4-yl, 1-(tetrahydropyran-(3 or 4)-yl)-piperidin-4-yl, 3-pyrrolidinyl, 3- or 4-piperidinyl or 3- or 4-hexahydroazepinyl (all optionally substituted by 1-3 1-4C alkyl)), 4-7 membered alkyleneimino (optionally substituted by 1-4 CH 3 or C 2H 5, and optionally substituted on a ring C atom or CH 3 or C 2H 5 substituent by R 5), piperidino (substituted by tetrahydrofuranyl, tetrahydropyranyl or tetrahydrofuranylmethyl), 6-7 membered alkyleneimino (optionally substituted with 1-2 CH 3 or C 2H 5 and containing O, S, NR 6, SO or SO 2 in place of CH 2 in the 4-position), imidazolyl (optionally substituted by 1-3 CH 3), or 5-7C cycloalkyl containing O, S NR 6, SO OR SO 2 in place of 1 CH 2; or D + E : H, F, Cl, 1-4C alkyl (optionally substituted by 1-5 F), 3-6C cycloalkyl, Ar, Het, 1-4C alkylcarbonyl, Ar-CO-, COOH, 1-4C alkoxycarbonyl, -CONH 2, -CONH(1-4C alkyl), -CON(1-4C alkyl) 2, or C(O) substituted with 4-7 membered alkyleneimino optionally containing O, S NR 6, SO or SO 2 in place of CH 2 in the 4-position when it is 6-7 membered; R c4-7C cycloalkoxy or 3-7C cycloalkoxy-1-6C alkoxy (each optionally ring-substituted with 1-3C alkyl, OH, 1-4C alkoxy, NH 2, (1-4C alkyl)NH-, (1-4C alkyl) 2N-, pyrrolidino, piperidino, morpholino, piperazino, N-(CH 3 or C 2H 5)-piperazino, CH 3 or C 2H 5 (all substituted by OH, 1-4C alkoxy, NH 2, (1-4C alkyl)NH-, (1-4C alkyl) 2N-, pyrrolidino, piperidino, morpholino, piperazino, N-(CH 3 or C 2H 5)-piperazino, and the monosubstituted cycloalkyl group is optionally substituted by 1-3C alkyl), tetrahydrofuran-3-yloxy, tetrahydropyran-(3 or 4)-yloxy, tetrahydrofuranylmethoxy, 2-4C alkoxy (substituted in the beta -, gamma - or delta -position by azetidin-1-yl or 4-(CH 3 or C 2H 5)-homopiperazino), or 3-pyrrolidinyloxy, 2- or 3-pyrrolidinyl-1-4C alkoxy, 3- or 4-piperidinyloxy, 2-, 3- or 4-piperidinyl-1-4C alkoxy, 3- or 4-hexahydro-azepinyloxy or 2-, 3- or 4-hexahydro-azepinyl-1-4C alkoxy (all N-substituted by R 6); R 4H or 1-4C alkyl; R 5OH, 1-4C alkoxy, NH 2, (1-4C alkyl)NH, (1-4C alkyl) 2N-, 4-7 membered alkyleneimino (optionally substituted with 1-2 CH 3 and optionally containing O, S, SO, SO 2, NH or N(1-4C alkyl) in place of CH 2 in the 4-position when it is 6-7 membered); R 6H, 1-4C alkyl, -CH 2-CH 2-OCH 3, -(CH 2) 3-OCH 3, 3-7C cycloalkyl; 3-7C cycloalkyl-1-4C alkyl, tetrahydrofuran-3-yl, tetrahydropyran-(3 or 4)-yl, tetrahydrofuranylmethyl, CHO, 1-4C alkylcarbonyl, 1-4C alkyl-SO 2-, -CONH 2, -CONH(1-4C alkyl), or -CON(1-4C alkyl) 2; Het : 5-membered heteroaryl containing NH, O or S and optionally 1-2 N, and optionally substituted by 1-2 CH 3 or C 2H 5, or 6-membered heteroaryl containing 1-3 N and optionally substituted by 1-2 CH 3 or C 2H 5 or by halo, CF 3, OH, OCH 3 or OC 2H 5; Ar : phenyl optionally substituted with R 7 or 1-3 R 8, or R 7 and 1-2 R 8; R 7CN, COOH, 1-4C alkoxycarbonyl, -CONH 2, -CONH(1-4C alkyl), -CON(1-4C alkyl) 2, 1-4C alkylthio, 1-4C alkyl-SO-, 1-4C alkyl-SO 2-, OH, 1-4C alkyl-SO 2-O-, CF 3O-, NO 2, NH 2, (1-4C alkyl)NH-, (1-4C alkyl) 2N-, 1-4C alkylcarbonyl-NH -, (1-4C alkyl)(1-4C alkylcarbonyl)N-, 1-4C alkyl-SO 2-NH-, 1-4C alkyl-SO 2-N(1-4C alkyl)-, SO 2-NH 2, -SO 2-NH(1-4C alkyl), -SO 2-N(1-4C alkyl), or C(O) (substituted by 5-7 membered alkyleneimino optionally containing O, S, SO, SO2 NH or N(1-4C alkyl) in place of the CH 2 in the 4-position when it is 6-7 membered); and R 8halo, 1-4C alkyl, CF 3, or 1-4C alkoxy; or 2R 8 on adjacent C atoms : 3-5C alkylene, methylenedioxy or 1,3-butadien-1,4-ylene. An independent claim is also included for the preparation of compounds (I). ACTIVITY : Cytostatic; antiasthmatic; antiinflammatory; gastrointestinal; antiulcer; dermatological; antipsoriatic. MECHANISM OF ACTION : Tyrosine kinase signal transduction inhibitor; epidermal growth factor receptor (EGF-R) signal transduction inhibitor. In an in vitro test for the inhibition of EGF-dependent cell proliferation, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline (Ia) had an IC 50 of 0.2 nM .